Abstract 4030: Generation of profound anti-tumor immunity by AUR-109, a spectrum-selective tyrosine kinase inhibitor, either as a single agent or in combination with immune checkpoint inhibitors
Authors: Girish Daginakatte, Saravanan Thiyagarajan, Kiran Aithal, Mamon Dey, Reshma Reghu, Monalisha Mandal, Kavitha Nellore, Susanta Samajdar, Murali Ramachandra
Journal: Cancer Research (2023)

Abstract AUR-109 is an orally bioavailable clinical stage receptor tyrosine kinase inhibitor (RTK) that inhibits the activity of proangiogenic and oncogenic pathway-related RTKs including DDR1, FGFR, VEGFR, PDGFR, and RET. DDR1 instigates immune exclusion by promoting collagen fiber alignment thereby altering extracellular matrix (ECM) components in tumor immune microenvironment (TIME). DDR1 expression inversely correlated with reduced immune cell infiltration in TIME leading to exhaustion of tumor-fighting immune cells, tumor escape, EMT and metastasis. FGFRs induce the expression the PD-L1 and VEGFRs promote the proliferation of regulatory T cells (Treg), inhibit T-cell development and maturation of dendritic cells. These findings suggest that the spectrum-selective inhibition of these RTKs by AUR-109 has the potential to strongly modulate the anti- tumor immune response. Clinically successful immune checkpoint inhibitors (ICI) (anti-PD1, anti-PD-L1, and anti-CTLA4 antibodies) block the pathways that inhibit immune cell activation thus stimulating immune responses against the tumor cells. Although ICIs show improved survival in patients with many types of cancers, they suffer from the lack of response in majority of patients along with the development of resistance to therapy. To overcome the resistance and improve the efficacy, a number of combinations of PD-1 blockade with other anticancer therapies are being evaluated. We have undertaken a detailed characterization of the anti-tumor immune response by AUR-109 either as a single agent or in combination with anti-PD1 antibodies. The effect of AUR-109 on CD4 T cells and Treg cells was evaluated in the Renca subcutaneous tumor model. Immune cell population in the blood and tumor microenvironment were analyzed by FACS. Anti-tumor efficacy was analyzed in both subcutaneous and orthotopic Renca syngeneic tumor models. AUR-109 treatment resulted in an increase of total and CD4 T cells. Higher ratio of total T cells to regulatory T cells was observed indicating that there is an increase in effector T cells. In the TILs, there was decrease in the expression of PD-1 and PD-L1 with a concomitant increase in IFN-γ expression on CD8 T cells and NK cells indicating a profound immune activation caused by AUR-109 within the tumor. These results demonstrate the therapeutic potential of AUR-109 in combination with PD-1 blockade in preclinical models and the results from the ongoing combination studies will be presented. Citation Format: Girish Daginakatte, Saravanan Thiyagarajan, Kiran Aithal, Mamon Dey, Reshma Reghu, Monalisha Mandal, Kavitha Nellore, Susanta Samajdar, Murali Ramachandra. Generation of profound anti-tumor immunity by AUR-109, a spectrum-selective tyrosine kinase inhibitor, either as a single agent or in combination with immune checkpoint inhibitors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4030.